US6492522B1 - Process and intermediates for production of donepezil and related compounds - Google Patents
Process and intermediates for production of donepezil and related compounds Download PDFInfo
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- US6492522B1 US6492522B1 US09/763,245 US76324501A US6492522B1 US 6492522 B1 US6492522 B1 US 6492522B1 US 76324501 A US76324501 A US 76324501A US 6492522 B1 US6492522 B1 US 6492522B1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the present invention relates to a new process for the preparation of acetylcholinesterase inhibitors (anti-AchE) such as Donepezil, to some novel intermediates used in this process and to their preparation.
- anti-AchE acetylcholinesterase inhibitors
- Dementia is a chronic progressive organic mental disorder in which there is disturbance of multiple higher cortical functions including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement.
- Alzheimer's Disease is the commonest cause of dementia and is characterized by degeneration of specific nerve cells, presence of neurotic plaques, and neurofibrillary tangles. Definitive diagnosis of Alzheimer's Disease requires demonstration of these characteristic pathological features in brain tissue, although in the vast majority of cases diagnosis is made on clinical grounds alone, where it is more correctly called Senile Dementia of the Alzheimer Type (SDAT).
- SDAT Senile Dementia of the Alzheimer Type
- Donepezil is a new drug treatment for use in mild to moderate dementia due to SDAT.
- Donepezil acts by inhibiting acetylcholine esterase, the enzyme responsible for metabolising acetylcholine, thereby enhancing neurotransmitter levels.
- the general synthetic route to compounds [X] comprises the condensation of cyclic aromatic ketones [XI] with 1-substituted-4-( ⁇ -formylalkyl)piperidines [XII] followed by reduction of the obtained compounds [XIII] (Scheme 1) (Sugimoto, H., et al., J. Med. Chem., v. 38, 481 (1995); Eisai Co., U.S. Pat. No. 5,100,901).
- the present invention relates to a process for preparing a compound of formula [I] or a salt thereof:
- R 1 is N-acyl-4-piperidyl; N-alkoxycarbonyl-4-piperidyl; 4-piperidyl; N-alkyl-4-piperidyl; N-benzyl-4-piperidyl; N-( ⁇ -aralkyl)-4-piperidyl; 4-pyridyl;
- R 4 , R 5 , R 6 and R 7 are identical or different and each represents hydrogen, straight-chain or branched alkyl, aryl, hydroxy, alkoxy, aryloxy, benzyloxy, acyloxy, alkylthio, arylthio, benzylthio, acylamino, phthalimido or halogen;
- n 1, 2 or 3;
- n 1, 2, 3, 4 or 5;
- R 1 , R 4 , R 5 , R 6 and R 7 , m and n are as defined above;
- R 2 is selected from a derivatised or non-derivatised carboxyl, cyano, N-substituted aminocarbonyl groups or hydrogen;
- R 3 is selected from a derivatised or non-derivatised carboxyl, cyano or N-substituted aminocarbonyl groups, optionally in the presence of acids and/or solvents.
- enantiomerically enriched compounds of formula [I] or salts thereof are prepared by cyclisation of optically pure compounds of formula [II], wherein R 2 and R 3 are different.
- the present invention also relates to new compounds of formula [II]:
- the present invention further relates to a process for preparing a compound [II] by the hydrogenation of a compound of formula [VIII] or [IX] or mixtures thereof
- R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , n and m are as defined above.
- a compound of the formula [II] can be prepared by reaction of a compound of formula [V]
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, m and n are as defined above.
- Scheme 2 refers to a process for the preparation of a compound of formula [I] or salts thereof by cyclisation of a compound of formula [II] or salts thereof:
- ester, amido, cyano or ether protecting groups can be hydrolyzed under the conditions of the cyclisation reaction either in the starting compound [II] or in the desired compound [I].
- the cyclisation is carried out with a previously hydrolysed compound [II], wherein R 2 is hydrogen or a carboxyl group and to R 3 is a carboxyl group.
- Compound [II] wherein R 2 and R 3 are carboxyl groups, are decarboxylated in the course of the intramolecular acylatin.
- the cyclisation of the present invention is carried out in the presence of protic acids or Lewis acids or a mixture thereof.
- protic acids or Lewis acids or a mixture thereof examples include trifluoromethanesulfonic acid, methanesulfonic acid, polyphosphoric acid, fluoro- or chlorosulfonic acid, sulfuric acid, hydrogen fluoride, hydrogen chloride, zinc chloride, zinc bromide, aluminium chloride, aluminium bromide, titanium chloride, boron fluoride, phosphorus pentoxide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thyonyl chloride and sulfuryl chloride.
- the cyclisaton of the present invention can be carried out in the presence of a solvent.
- the solvent is selected from dichloromethane, chloroform, dichloroethane, tetrachloroethane, chlorobenzene, dichlorobenzene, nitromethane, nitroethane, nitrobenzene, ether or mixtures thereof.
- the present invention relates to new compounds of formula [II] including the optically active enantiomers thereof (R 2 ⁇ R 3 ) which are used in the cyclisation shown in Scheme 2 above.
- X represents a facile leaving group and may be a sulfonate group or a halogen.
- X is selected from chlorine and bromine.
- the reactions according to Scheme 5 are usually carried out in the presence of a strong base, as for example metal alkoxides, metal amides, metal hydrides or mixtures thereof.
- a strong base as for example metal alkoxides, metal amides, metal hydrides or mixtures thereof.
- the strong base is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, sodium tert-pentoxide, sodium bis(trimethylsilyl)amide, lithium diisopropylamide or mixtures thereof.
- the coupling reaction according to Scheme 6 is usually carried out in the presence of a base.
- the base is selected from metal carbonate, metal alkoxides, metal amides or metal hydrides. More preferably, the base is selected from potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide or mixture thereof.
- the above process can be carried out either without a solvent or in the presence of an organic solvent or water.
- the organic solvent is preferably selected from tetrahydrofuran (THF), 1,2-dimethoxyethane, dichloromethane, benzene, toluene, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, dimethylsulphoxide (DMSO), methanol, ethanol, isopropanol, tert-butyl alcohol or mixtures thereof.
- the compounds [VIII] and [IIX] in Scheme 6 can be reduced by catalytic hydrogenation.
- Transition metals can be used as catalysts in said catalytic hydrogenation.
- Pd, Pt, Rh, Ru or Ni are used.
- some of the R 1 groups are reduced (e.g. 4-pyridyl—to 4-piperidyl. In such a case it is preferred to protect the nitrogen of the piperidyl group).
- a compound of formula [IIa] (Scheme 3) may be prepared from the compounds [IIIa] and [IVa], as shown in the following Schemes 7 and 8.
- Enantiomerically enriched compounds of formula [I] are obtained from optically pure compounds [II] (Scheme 2), which in turn, are obtained from a racemic mixture of [II] (wherein R 2 ⁇ R 3 ) by either of the following reactions:
- the undesired enantiomer may be racemised and reused.
- reaction mixture was concentrated under reduced pressure to about half volume and treated with a mixture of ice and 5% aqueous citric acid followed by the neutralisation with 5% aqueous sodium hydrogen carbonate solution.
- Phosphorous pentoxide (1.0 g) was dissolved in methanesulfonic acid (10.0 g) at 90° C. (3,4-Dimethoxybenzyl)(N-benzyl-4-piperidylmethyl)malonic acid p-toluenesulfonate [XVa] (2.0 g) were added to the solution at 55° C. The mixture was stirred vigorously for 2 hours at 55-65° C. and poured on crushed ice. The obtained mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
- donepezil was purified by column chromatography on silica gel (dichloromethane methanol from 100:0 to 96:4 v/v) to give donepezil [VII].
- 1 H NMR is in agreement with the literature.
- reaction mixture was concentrated under reduced pressure to about half volume and treated with a mixture of ice and 5% aqueous citric acid followed by neutralization with aqueous sodium hydrogen carbonate solution.
- Phosphorous pentoxide (1.0 g) was added to methanesulfonic acid (10.0 g, 104 mmol) and the mixture was stirred at 90° C. to complete dissolution of phosphorous pentoxide.
- the mixture was cooled to 55° C. and (3,4-dimethoxybenzyl)(N-benzyl4-piperidylmethyl)malonic acid [XV] (2.0 g) was added over a period of 10 min.
- the obtained mixture was stirred vigorously for 2 hours at 55-65° C.
- the reaction mixture was poured into crushed ice and extracted with dichloromethane. The organic layer was washed with aqueous sodium carbonate, dried over sodium sulfate, filtered and concentrated under reduced pressure.
- a 10 L glass reactor equipped with a mechanical stirrer, a digital thermometer, a heating mantle and a reflux condenser, connected to a distillation head was charged with triethyl phosphite (3.69 Kg, 22.2 mol) and ethyl chloroacetate (2.72 Kg, 22.2 mol).
- the reactor was filled with argon and the reaction mixture was heated to 120° C.
- the stirring was continued for 3 hours and the temperature of the solution was raises to 165° C., during this time some triethyl phosphite and ethyl chloroacetate was distilled off.
- the reaction mixture was heated to 174° C. and the solution was left overnight.
- the reaction mixture was fractionationally distilled under reduced pressure (10-11 mbar) to give 4.43 Kg (89.3% yield) triethyl phosphoacetate with 98.2% purity by GC.
- a 100 L glass reactor equipped with a mechanical stirrer, a dropping funnel, a thermometer and a bubbler was charged with veratraldehyde (3.45 Kg, 20.8 mol), triethyl phosphonoacetate (4.65 Kg, 20.7 mol) and dichloromethane (53.5 Kg) and filled with argon.
- the solution of titanium (IV) chloride (7.87 Kg, 41.5 mol) in dichloromethane (16.2 Kg) was added dropwise to the stirred mixture while keeping the temperature between ⁇ 5° and 0° C. The mixture was stirred for an additional 2 hours at the same temperature.
- Triethylamine (8.40 Kg, 83.0 mol) was added dropwise to the stirred mixture for three hours while keeping the temperature between ⁇ 5 and 0° C. The obtained mixture was stirred for an additional 0.5 hour at the same temperature.
- the reaction mixture was poured under stirring into water at 20 ⁇ 25° C. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic extracts were consequently washed with water, sodium hydrogencarbonate aqueous solution and again with water.
- a 18 L stainless steel high pressure “Parr” reactor was charged with 10 wt. % palladium on activated carbon (175 g), sodium acetate (262 g), glacial acetic acid (480 g), a mixture of [XXVa] and [XXVIa] (1200 g, 3.67 mol), abs. ethanol (12 L) and filled consequently with nitrogen and hydrogen.
- the hydrogenation was carried out at hydrogen pressure of 250 psi at 90° C.
- the reactor was cooled to room temperature and the catalyst was filtered off (the catalyst may be used repeatedly in following reactions).
- the obtained solution of [XXVIIa] was used for the next step without further purification.
- a 20 L glass reactor, equipped with a heating mantle, a mechanical stirrer, a thermometer, a dropping funnel and a condenser connected to a bubbler was charged with the solution of [XXVIIa] from the previous step, sodium carbonate (1.35 Kg, 12.7 mol) and benzyl chloride (743.0 g, 5.87 mol) and filled with argon.
- the mixture was stirred at 60-65° C. for 8 h and evaporated under reduced pressure. Water (6.0 Kg) and toluene (3.8 Kg) were added to the residue.
- the mixture was stirred at room temperature until complete disappearance of solid phase.
- the organic layer was separated and the aqueous layer was extracted with toluene.
- the combined organic solution was extracted with 20% aqueous solution of citric acid (7.8 Kg).
- the aqueous solution was basified to pH 10 with sodium carbonate and extracted with dichloromethane.
- the organic extract was dried over sodium sulfate, filtered, passed through short silica gel column and evaporated under reduced pressure to give 1.82 Kg (80% yield from the mixture of compounds [XXVa] and [XXVIa]) of the compound [XVIIa] as yellow oil with 96.7% purity by GC.
- a 50 L glass reactor equipped with a mechanical stirrer, a dropping funnel, a thermometer and a condenser connected to a bubbler was charged with phosphorus pentoxide (1.40 Kg) and methanesulfonic acid (13.37 Kg) and filled with argon. The mixture was stirred at 70-80° C. until complete homogenization. Dichloromethane (4.0 Kg) and 2-(3,4-dimethoxybenzyl)-3-(N-benzyl-4-piperidine)propionic acid [XVI] (2.50 Kg, 6.29 mol) were added to the mixture at 35-40° C. The obtained mixture was stirred under reflux for 1.5 hour.
- a 100 L glass reactor equipped with a mechanical stirrer was charged with crushed Ice (18.0 kg) and filled with argon.
- the cold reaction mixture was added to the ice and the mixture was stirred for 15 min.
- the aqueous layer of the mixture was adjust to pH 8.0 by addition potassium hydroxide to the stirred mixture at 10-15° C.
- the organic layer was separated and the aqueous layer was extracted with dichloromethane.
- the combined organic extracts were dried over sodium sulfate, passed through short silica gel column and evaporated under reduced pressure.
- the residue* (2.40 Kg, quantitative yield, one spot on TLC) was dissolved in diisopropyl ether. The obtained solution was kept overnight at room temperature and 2 hours at 0-5° C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL12580998A IL125809A (en) | 1998-08-17 | 1998-08-17 | Process and intermediates for production of donepezil and related compounds |
IL125809 | 1998-08-17 | ||
PCT/IL1999/000436 WO2000009483A2 (fr) | 1998-08-17 | 1999-08-11 | Nouveau procede et intermediaires pour la production de donepezil et de ses composes apparentes |
Publications (1)
Publication Number | Publication Date |
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US6492522B1 true US6492522B1 (en) | 2002-12-10 |
Family
ID=11071859
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/763,245 Expired - Fee Related US6492522B1 (en) | 1998-08-17 | 1999-08-11 | Process and intermediates for production of donepezil and related compounds |
Country Status (7)
Country | Link |
---|---|
US (1) | US6492522B1 (fr) |
EP (1) | EP1129073A2 (fr) |
JP (1) | JP2002525264A (fr) |
AU (1) | AU5191099A (fr) |
HU (1) | HUP0103253A3 (fr) |
IL (1) | IL125809A (fr) |
WO (1) | WO2000009483A2 (fr) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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US20040192919A1 (en) * | 2002-08-14 | 2004-09-30 | Finetech Laboratories, Ltd. | Process for production of highly pure donepezil hydrochloride |
WO2005003092A1 (fr) * | 2003-07-01 | 2005-01-13 | Hetero Drugs Limited | Preparation d'intermediaires pour inhibiteurs de l'acetyl cholinesterase |
US20050228019A1 (en) * | 2004-01-26 | 2005-10-13 | Cortex Pharmaceuticals, Inc. | Enhancement of ampakine-Induced facilitation of synaptic responses by cholinesterase inhibitors |
US20060058336A1 (en) * | 2003-02-27 | 2006-03-16 | Shigetada Nakanishi | Pharmaceutical composition for treatment of drug dependence |
EP1669349A1 (fr) * | 2004-12-08 | 2006-06-14 | Chemagis Ltd. | Nouvelles formes cristallines de la base de donepezil |
EP1992616A1 (fr) | 2005-07-30 | 2008-11-19 | Pliva Hrvastka D.O.O. | Procédé de préparation de donépézil et composants intermédiaires associés |
CN100436416C (zh) * | 2005-07-29 | 2008-11-26 | 西南合成制药股份有限公司 | 盐酸多奈哌齐合成工艺 |
US20080306271A1 (en) * | 2005-12-20 | 2008-12-11 | Jozsef Neu | Novel Process for Production of Highly Pure Polymorph (I) Donepezil Hydrochloride |
US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
WO2011151359A1 (fr) | 2010-06-02 | 2011-12-08 | Noscira, S.A. | Traitement combiné comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione |
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IL150982A (en) * | 2002-07-30 | 2007-02-11 | Ori Lerman | Process for making Donafzil |
IL151253A0 (en) * | 2002-08-14 | 2003-04-10 | Finetech Lab Ltd | Process for production of highly pure donepezil hydrochloride |
ES2354737T3 (es) * | 2006-01-04 | 2011-03-17 | Cipla Limited | Procedimiento y producto intermedio para la preparación de donepezylo. |
EP2089383B1 (fr) | 2006-11-09 | 2015-09-16 | Probiodrug AG | Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies |
DK2091948T3 (da) | 2006-11-30 | 2012-07-23 | Probiodrug Ag | Nye inhibitorer af glutaminylcyclase |
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CA2679446C (fr) | 2007-03-01 | 2016-05-17 | Probiodrug Ag | Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase |
US9656991B2 (en) | 2007-04-18 | 2017-05-23 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
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JP5688745B2 (ja) | 2010-03-10 | 2015-03-25 | プロビオドルグ エージー | グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤 |
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ES2812698T3 (es) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3476759A (en) | 1967-05-02 | 1969-11-04 | Mcneilab Inc | 2- and 3-(4-piperidyl) indanes and indanols |
US5100901A (en) | 1987-06-22 | 1992-03-31 | Eisai Co., Ltd. | Cyclic amine compounds and pharmaceutical use |
WO1997022584A1 (fr) | 1995-12-15 | 1997-06-26 | Pfizer Inc. | Procedes de preparation de 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine et intermediaires utilises a cet effet |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2893893B2 (ja) * | 1990-02-02 | 1999-05-24 | 三菱化学株式会社 | 環状ケトン類の製造方法 |
-
1998
- 1998-08-17 IL IL12580998A patent/IL125809A/xx not_active IP Right Cessation
-
1999
- 1999-08-11 JP JP2000564937A patent/JP2002525264A/ja active Pending
- 1999-08-11 HU HU0103253A patent/HUP0103253A3/hu unknown
- 1999-08-11 AU AU51910/99A patent/AU5191099A/en not_active Abandoned
- 1999-08-11 EP EP99936948A patent/EP1129073A2/fr not_active Withdrawn
- 1999-08-11 WO PCT/IL1999/000436 patent/WO2000009483A2/fr not_active Application Discontinuation
- 1999-08-11 US US09/763,245 patent/US6492522B1/en not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3476759A (en) | 1967-05-02 | 1969-11-04 | Mcneilab Inc | 2- and 3-(4-piperidyl) indanes and indanols |
US5100901A (en) | 1987-06-22 | 1992-03-31 | Eisai Co., Ltd. | Cyclic amine compounds and pharmaceutical use |
EP0742207A1 (fr) | 1987-06-22 | 1996-11-13 | Eisai Co., Ltd. | 4-(Indan-1-one-2-yl-alkyl)-1-phénylalkyl-pipéridines et procédés pour leur préparation |
WO1997022584A1 (fr) | 1995-12-15 | 1997-06-26 | Pfizer Inc. | Procedes de preparation de 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine et intermediaires utilises a cet effet |
Non-Patent Citations (4)
Title |
---|
Derwent AbstractXP-002120528, of "JP 03 279343 A" published Dec. 10, 1991 assigned to Mitsubishi Kasei Corp. 4, Derwent Publications Ltd. |
Hachiro Sugimoto et al., "Synthesis and Structure-Activity Relationships of Acetylcholinesterase Inhibitors: 1-Benzyl-4-[(5,6-deimethoxy-1-oxoindan-2-yl)methyl]piperidine Hydrochloride and Related Compounds", J. Med. Chem. vol. 38, pp. 4821-4829, 1995. |
Hideto Miyoshi et al., "Specificity of Pyridinum Inhibitors of the Ubiquinone Reduction Sites In Mitochondrial Complex I", Journal of Biological Chemistry, vol. 273, n. 28, pp. 17368-17374, 1998. |
Saul Patai: "The Chemistry of the Carbonyl Group", Interscience Publishers, pp. 252-255 and 298-299, 1966. |
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US20040192919A1 (en) * | 2002-08-14 | 2004-09-30 | Finetech Laboratories, Ltd. | Process for production of highly pure donepezil hydrochloride |
US20060058336A1 (en) * | 2003-02-27 | 2006-03-16 | Shigetada Nakanishi | Pharmaceutical composition for treatment of drug dependence |
WO2005003092A1 (fr) * | 2003-07-01 | 2005-01-13 | Hetero Drugs Limited | Preparation d'intermediaires pour inhibiteurs de l'acetyl cholinesterase |
US20060041140A1 (en) * | 2003-07-01 | 2006-02-23 | Hetero Drugs Limited | Preparation of intermediates for acetyl cholinesterase inhibitors |
US7446203B2 (en) | 2003-07-01 | 2008-11-04 | Hetero Drugs Limited | Preparation of intermediates for acetycholinesterase inhibitors |
US20050228019A1 (en) * | 2004-01-26 | 2005-10-13 | Cortex Pharmaceuticals, Inc. | Enhancement of ampakine-Induced facilitation of synaptic responses by cholinesterase inhibitors |
EP1935884A3 (fr) * | 2004-12-08 | 2008-07-09 | Chemagis Ltd. | Nouvelles formules cristallines à base de donépézil |
US20080194827A1 (en) * | 2004-12-08 | 2008-08-14 | Chemagis Ltd. | Crystalline forms of Donepezil base |
EP1669349A1 (fr) * | 2004-12-08 | 2006-06-14 | Chemagis Ltd. | Nouvelles formes cristallines de la base de donepezil |
CN100436416C (zh) * | 2005-07-29 | 2008-11-26 | 西南合成制药股份有限公司 | 盐酸多奈哌齐合成工艺 |
EP1992616A1 (fr) | 2005-07-30 | 2008-11-19 | Pliva Hrvastka D.O.O. | Procédé de préparation de donépézil et composants intermédiaires associés |
US20090137811A1 (en) * | 2005-07-30 | 2009-05-28 | Pliva Hrvatska D.O.O | Process for the preparation of donepezil and intermediate compounds thereof as well as hydrates of donepezil |
US20080306271A1 (en) * | 2005-12-20 | 2008-12-11 | Jozsef Neu | Novel Process for Production of Highly Pure Polymorph (I) Donepezil Hydrochloride |
US20100113793A1 (en) * | 2006-03-20 | 2010-05-06 | Ind-Swift Laboratories Limited | Process for the Preparation of Highly Pure Donepezil |
WO2011151359A1 (fr) | 2010-06-02 | 2011-12-08 | Noscira, S.A. | Traitement combiné comprenant un inhibiteur de la cholinestérase et un dérivé de thiadiazolidinedione |
Also Published As
Publication number | Publication date |
---|---|
HUP0103253A3 (en) | 2002-02-28 |
IL125809A (en) | 2005-08-31 |
WO2000009483A3 (fr) | 2001-06-21 |
WO2000009483A2 (fr) | 2000-02-24 |
EP1129073A2 (fr) | 2001-09-05 |
JP2002525264A (ja) | 2002-08-13 |
HUP0103253A2 (hu) | 2002-01-28 |
AU5191099A (en) | 2000-03-06 |
IL125809A0 (en) | 1999-04-11 |
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